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Identification and Characterization of the Amphioxus Lck and Its Associated Tyrosine Phosphorylation-Dependent Inhibitory LRR Receptor.

التفاصيل البيبلوغرافية
العنوان: Identification and Characterization of the Amphioxus Lck and Its Associated Tyrosine Phosphorylation-Dependent Inhibitory LRR Receptor.
المؤلفون: Zhou J; Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China., Xiao Z; Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China., Zhan Y; Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China., Qu X; Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China., Mou S; Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China., Deng C; Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China., Zhang T; Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China., Lan X; Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China., Huang S; Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China., Li Y; Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
المصدر: Frontiers in immunology [Front Immunol] 2021 Jun 03; Vol. 12, pp. 656366. Date of Electronic Publication: 2021 Jun 03 (Print Publication: 2021).
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [Lausanne : Frontiers Research Foundation]
مواضيع طبية MeSH: Costimulatory and Inhibitory T-Cell Receptors/*metabolism , Lancelets/*metabolism , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/*metabolism, Animals ; Biomarkers ; Cloning, Molecular ; Costimulatory and Inhibitory T-Cell Receptors/genetics ; Databases, Genetic ; Enzyme-Linked Immunosorbent Assay ; Gene Expression Profiling ; High-Throughput Nucleotide Sequencing ; Humans ; Immunophenotyping ; Interleukin-2/biosynthesis ; Jurkat Cells ; Lancelets/genetics ; Lymphocyte Activation ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/genetics ; Phosphorylation ; Rabbits ; Receptors, Antigen, T-Cell/metabolism ; Sequence Analysis, DNA ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism
مستخلص: Amphioxus (e.g., Branchiostoma belcheri , Bb) has recently emerged as a new model for studying the origin and evolution of vertebrate immunity. Mammalian lymphocyte-specific tyrosine kinase (Lck) plays crucial roles in T cell activation, differentiation and homeostasis, and is reported to phosphorylate both the ITIM and ITSM of PD-1 to induce the recruitment of phosphatases and thus the inhibitory function of PD-1. Here, we identified and cloned the amphioxus homolog of human Lck. By generating and using an antibody against BbLck, we found that BbLck is expressed in the amphioxus gut and gill. Through overexpression of BbLck in Jurkat T cells, we found that upon TCR stimulation, BbLck was subjected to tyrosine phosphorylation and could partially rescue Lck-dependent tyrosine phosphorylation in Lck-knockdown T cells. Mass spectrometric analysis of BbLck immunoprecipitates from immunostimulants-treated amphioxus, revealed a BbLck-associated membrane-bound receptor LRR (BbLcLRR). By overexpressing BbLcLRR in Jurkat T cells, we demonstrated that BbLcLRR was tyrosine phosphorylated upon TCR stimulation, which was inhibited by Lck knockdown and was rescued by overexpression of BbLck. By mutating single tyrosine to phenylalanine (Y-F), we identified three tyrosine residues (Y539, Y655, and Y690) (3Y) of BbLcLRR as the major Lck phosphorylation sites. Reporter gene assays showed that overexpression of BbLcLRR but not the BbLcLRR-3YF mutant inhibited TCR-induced NF-κB activation. In Lck-knockdown T cells, the decline of TCR-induced IL-2 production was reversed by overexpression of BbLck, and this reversion was inhibited by co-expression of BbLcLRR but not the BbLcLRR-3YF mutant. Sequence analysis showed that the three tyrosine-containing sequences were conserved with the tyrosine-based inhibition motifs (ITIMs) or ITIM-like motifs. And TCR stimulation induced the association of BbLcLRR with tyrosine phosphatases SHIP1 and to a lesser extent with SHP1/2. Moreover, overexpression of wild-type BbLcLRR but not its 3YF mutant inhibited TCR-induced tyrosine phosphorylation of multiple signaling proteins probably via recruiting SHIP1. Thus, we identified a novel immunoreceptor BbLcLRR, which is phosphorylated by Lck and then exerts a phosphorylation-dependent inhibitory role in TCR-mediated T-cell activation, implying a mechanism for the maintenance of self-tolerance and homeostasis of amphioxus immune system and the evolutionary conservatism of Lck-regulated inhibitory receptor pathway.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2021 Zhou, Xiao, Zhan, Qu, Mou, Deng, Zhang, Lan, Huang and Li.)
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فهرسة مساهمة: Keywords: TCR-mediated T cell activation; amphioxus; amphioxus Lck associated LRR (BbLcLRR); immunoreceptor tyrosine-based inhibitory motif; leucine rich repeat receptor (LRR); lymphocyte-specific tyrosine kinase (Lck); tyrosine phosphorylation; tyrosine phosphorylation-dependent inhibitory immunoreceptor
المشرفين على المادة: 0 (Biomarkers)
0 (Costimulatory and Inhibitory T-Cell Receptors)
0 (Interleukin-2)
0 (Receptors, Antigen, T-Cell)
EC 2.7.10.2 (Lymphocyte Specific Protein Tyrosine Kinase p56(lck))
تواريخ الأحداث: Date Created: 20210621 Date Completed: 20210928 Latest Revision: 20210928
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC8211107
DOI: 10.3389/fimmu.2021.656366
PMID: 34149695
قاعدة البيانات: MEDLINE
الوصف
تدمد:1664-3224
DOI:10.3389/fimmu.2021.656366